Usage
- Gemigliptin + Metformin is prescribed for type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise to improve glycemic control in adults. It is specifically indicated for patients who have inadequate glycemic control on metformin monotherapy, or in combination with sulfonylurea or insulin. It can also be considered as initial therapy in treatment-naive patients who are inadequately controlled by diet and exercise alone.
- Pharmacological classification: Antidiabetic agent; Dipeptidyl peptidase-4 (DPP-4) inhibitor combined with a biguanide.
- Mechanism of action: Gemigliptin is a DPP-4 inhibitor that works by increasing incretin levels (GLP-1 and GIP). These incretins stimulate glucose-dependent insulin release, suppress glucagon secretion, and slow gastric emptying. Metformin improves insulin sensitivity in the liver and peripheral tissues and decreases hepatic glucose production.
Alternate Names
- It is commonly known as Gemigliptin and Metformin fixed-dose combination (FDC).
- Brand names: Zemimet SR, Zemiglo
How It Works
- Pharmacodynamics: Gemigliptin inhibits DPP-4, leading to increased GLP-1 and GIP levels, which enhance insulin secretion and decrease glucagon levels. Metformin reduces hepatic glucose production, improves peripheral insulin sensitivity, and decreases intestinal glucose absorption. The combined effect results in improved glycemic control.
- Pharmacokinetics: Gemigliptin is metabolized primarily by CYP3A4, with a half-life of approximately 17 hours. Metformin is not metabolized and is excreted unchanged by the kidneys, with a half-life of 4-8.7 hours.
- Mode of action: Gemigliptin competitively binds to and inhibits DPP-4, preventing the degradation of incretins. Metformin’s exact mechanism is unclear, but it is thought to activate AMP-activated protein kinase (AMPK), which leads to decreased hepatic gluconeogenesis and increased peripheral glucose uptake.
- Elimination pathways: Gemigliptin is eliminated through a combination of hepatic metabolism and renal/fecal excretion. Metformin is primarily excreted unchanged in the urine.
Dosage
Standard Dosage
Adults:
- Initial dose: Gemigliptin 50 mg + Metformin 500 mg once daily.
- Maintenance dose: Can be increased up to Gemigliptin 50 mg + Metformin 2000 mg per day, as needed to achieve glycemic control. The dose can be taken with or without food. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Children:
- Not recommended for use in children. Pediatric safety and efficacy have not been established.
Special Cases:
- Elderly Patients: Use with caution as age increases, due to potential age-related decline in renal function. Monitor renal function carefully.
- Patients with Renal Impairment: Contraindicated in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2). Not recommended for initiation in patients with eGFR 30-60 mL/min/1.73 m2, and continued use is not recommended if eGFR persists in this range.
- Patients with Hepatic Dysfunction: No dosage adjustment required.
- Patients with Comorbid Conditions: Use with caution in patients with heart failure. Avoid in patients with conditions predisposing to lactic acidosis.
Clinical Use Cases
- Not specifically indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
- Adjust dose based on renal function and glycemic control. Monitor renal function periodically.
Side Effects
Common Side Effects
- Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain.
- Upper respiratory tract infection, nasopharyngitis.
Rare but Serious Side Effects
- Lactic acidosis (metformin component).
- Hypersensitivity reactions (gemigliptin component): Angioedema, anaphylaxis.
- Pancreatitis (gemigliptin component).
- Hypoglycemia (especially with concomitant sulfonylurea).
Long-Term Effects
- Potential for vitamin B12 deficiency (metformin component).
Adverse Drug Reactions (ADR)
- Lactic acidosis, acute pancreatitis, severe hypersensitivity reactions.
Contraindications
- Severe renal impairment (eGFR < 30 mL/min/1.73 m2).
- Hypersensitivity to gemigliptin or metformin.
- Diabetic ketoacidosis.
- Type 1 diabetes.
- Acute or chronic metabolic acidosis.
Drug Interactions
- CYP450 interactions: Gemigliptin is metabolized by CYP3A4. Strong CYP3A4 inducers (rifampicin, phenytoin, carbamazepine) are not recommended.
- Other clinically significant interactions: Co-administration of gemigliptin with metformin may decrease the Cmax of metformin but does not significantly affect its AUC. Pioglitazone AUC and Cmax may decrease.
- Interactions with commonly prescribed medications: Caution with alcohol (increased risk of lactic acidosis with metformin).
- OTC drugs/supplements: Avoid concomitant use of medications that may impair renal function.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Not assigned. Gemigliptin + Metformin is generally not recommended during pregnancy. There are no adequate and well-controlled studies in pregnant women. If pregnancy is detected, consider switching to insulin.
- Breastfeeding: It is unknown if gemigliptin or metformin is excreted in breast milk. Not generally recommended while breastfeeding.
Drug Profile Summary
- Mechanism of Action: Gemigliptin: DPP-4 inhibitor, increases incretin levels. Metformin: reduces hepatic glucose output and increases peripheral insulin sensitivity.
- Side Effects: GI upset, upper respiratory infection, hypoglycemia, lactic acidosis (rare), pancreatitis (rare), hypersensitivity reactions (rare).
- Contraindications: Severe renal impairment, hypersensitivity, diabetic ketoacidosis, type 1 diabetes.
- Drug Interactions: CYP3A4 inducers, medications impacting renal function.
- Pregnancy & Breastfeeding: Generally not recommended.
- Dosage: Adults: 50mg/500mg up to 50mg/2000mg daily. Children: Not recommended.
- Monitoring Parameters: HbA1c, fasting and postprandial glucose, renal function, vitamin B12 levels (long-term metformin use).
Popular Combinations
- Often combined with sulfonylureas or insulin when dual therapy with metformin alone is insufficient.
Precautions
- Monitor renal function, especially in elderly patients.
- Assess and correct volume status before initiating in patients at risk of hypotension (e.g. those with renal impairment or on diuretics).
- Monitor for and assess ketoacidosis if suspected.
- Consider discontinuation in settings of reduced oral intake or fluid loss.
- Counsel patients about the symptoms of lactic acidosis and pancreatitis.
- Educate on the importance of adhering to diet and exercise recommendations.
FAQs (Frequently Asked Questions)
A: The initial recommended dose is 50 mg gemigliptin and 500 mg metformin once daily. This can be titrated upward to a maximum of 50 mg gemigliptin and 2000 mg metformin, based on the patient’s individual needs and tolerability.
A: Common side effects include gastrointestinal issues such as nausea, vomiting, diarrhea, and abdominal pain, as well as upper respiratory tract infections.
A: Gemigliptin + Metformin offers the combined benefits of a DPP-4 inhibitor and a biguanide in a single tablet. This offers multiple mechanisms of action impacting insulin secretion, glucagon secretion, and insulin sensitivity. This dual action can improve patient compliance and aid patients who do not respond to Metformin alone.
A: It is contraindicated in patients with severe renal impairment (eGFR <30 ml/min/1.73 m2). Use cautiously in patients with mild to moderate renal impairment, monitoring renal function regularly and adjusting the dose as needed.
A: Yes, monitor HbA1c, fasting and postprandial glucose levels, renal function, and vitamin B12 levels, especially during long-term metformin use.
Q6: Can this medication be used during pregnancy or breastfeeding?
A: Gemigliptin + Metformin is generally not recommended during pregnancy or breastfeeding. Discuss alternative therapies with your patient.
Q7: What should I do if my patient misses a dose?
A: They should take the missed dose as soon as they remember, unless it is close to the time of their next scheduled dose. Patients should not double up on doses.
A: It should be stored at room temperature (1-30°C) in a tightly closed container, away from moisture and direct sunlight.
A: The medication is generally weight neutral, unlike some other diabetes medications.
A: No, it is contraindicated in type 1 diabetes and diabetic ketoacidosis. It is indicated only for type 2 diabetes.
